tbuckley/cabot-search huggingface dataset:
Abstract P1138: Transcriptomic Insights Into How Previously Increased Cardiac Protein O-GlcNAcylation Enhances Susceptibility To Cardiac Dysfunction In A Response To Pressure-Overload
Authors: Samuel F Chang, Chae-Myeong Ha, Manoja Brahma, Luke Potter, Sayan Bakshi, John C Chatham, Adam R Wende
Journal: Circulation Research (2023)

Increased levels of cardiac protein posttranslational β-linked N-acetylglucosamine (O-GlcNAc) modification are implicated in adverse remodeling seen in hypertrophy and diabetes. Our previous work found elevated O-GlcNAc levels in hearts from diabetic mice, and a chronic increase in O-GlcNAc caused adverse cardiac remodeling. In diabetes, increased cardiac disease risk persists even after patients return to tight glycemic control. Thus, we hypothesize that a transient increase in O-GlcNAc is sufficient to exacerbate adverse cardiac remodeling under subsequent pressure-overload, and we propose that this is due to epigenetic modifications causing persistent changes in gene expression. We used an inducible, cardiomyocyte specific, dominant negative O-GlcNAcase (dnOGA) mouse. After a 2-wk induction (which leads to a 1.8-fold increase in O-GlcNAc levels) and subsequent 2-wk washout, Control (Con) and dnOGA mice undergo transverse-aortic constriction (TAC) or Sham surgery. After 8-wks, cardiac function is measured via echocardiography, gravimetric measures at harvest, and RNA-seq analysis is done on cardiac tissue. In both Con+TAC and dnOGA+TAC vs. Sham groups, systolic function is decreased ( -12%, p &lt; 0.001, -11%, p &lt; 0.01 ), and ventricular weight is increased ( +43%, +69%, both p &lt; 0.0001 ), consistent with cardiac hypertrophy. Interestingly, we see further exacerbation of cardiac hypertrophy ( +29%, p &lt; 0.0001 ) and pulmonary edema ( +36%, p &lt; 0.01 ) between dnOGA+TAC vs. Con+TAC groups. Also, RNA-seq results show distinct transcriptomic profiles between the experimental groups via hierarchical clustering ( |FC| &gt; 1.50, FDR &lt; 0.1 ). A candidate gene approach shows enhanced and exacerbated changes in genes associated with cardiac disease states like heart failure and fibrosis (e.g., Atp2a2, Col1a1, &amp; Nox4 ), consistent with cardiac remodeling. Our results support the hypothesis that transient increase in cardiac O-GlcNAc levels increases susceptibility to subsequent cardiac pathology. Moreover, the exacerbation of pathology is consistent with epigenetic mediated effects of transient O-GlcNAc induction; and pertaining to diabetes, provide a possible mechanism into the continued increased of cardiac disease risk.
Abstract P2003: Cardiomyocyte Polyploidy: Friend Or Foe?
Authors: Archan Chakraborty, Matthew Wolf, Donald Fox
Journal: Circulation Research (2023)

Developmental polyploidization (whole genome duplication) of cardiomyocytes is well conserved across mammals, birds and Drosophila . However, it is unclear whether precise control of cardiomyocyte polyploidy is essential. We found that there is a chamber-specific asymmetry to cardiomyocyte polyploidy in the Drosophila cardiac organ which is regulated by differential sensitivity of Insulin signaling. Higher ploidy cardiomyocytes correspond to the heart chamber, while lower ploidy cardiomyocytes correspond to the aorta chamber. Using immunofluorescence staining (IF), optical coherence tomography (OCT) and live imaging, we found that reducing chamber-specific ploidy affects cardiac function and reduces the velocity of circulating hemocytes, which indicates systemic heart failure. Intriguingly using human donor heart samples, we found that chamber specific asymmetry in cardiomyocyte ploidy and insulin sensitivity is similar to Drosophila . Our findings suggest that precise control of ploidy levels for cardiac organ sculpting is conserved across species. Polyploidization may have negative effects on cardiomyocyte regeneration, but our results suggest that region-specific control of ploidy levels is important for organ development and functionally.
Transcatheter aortic valve replacement in quadricuspid aortic valve: the crucial role of three-dimensional simulation in risk assessment
Authors: Yusuke Oba, Hiroshi Funayama, Masafumi Sato, Hisaya Kobayashi, Kenji Harada, Mamoru Arakawa, Koji Kawahito, Kazuomi Kario
Journal:  (2023)
Macrophage Membrane‐Camouflaged Aggregation‐Induced Emission Nanoparticles Enhance Photodynamic‐Immunotherapy to Delay Postoperative Tumor Recurrence
Authors: Zijuan Meng, Tingting Wang, Yuxin Hu, Hanzhi Ouyang, Quan Wang, Meng Wu, Jian Zhou, Xiaoding Lou, Shixuan Wang, Jun Dai, Fan Xia
Journal: Advanced Healthcare Materials (2023)

Abstract Surgery is a traditional tumor treatment, and immunotherapy can reduce the postoperative recurrence of tumors. However, the intrinsic limits of low responsive rate and non‐tumor specificity of immunotherapy agents are still insufficient to address therapeutic demands. Herein, the macrophages membrane camouflaged nanoparticles (NPs), named M@PFC, consisting of the aggregation‐induced emission photosensitizer (PF3‐PPh 3 ) and immune adjuvant (CpG), are reported. As the protein on the membrane interacts with the vascular cell adhesion molecule 1 (VCAM‐1) of cancer cells, M@PFC efficiently transports CpG to the tumor. Meanwhile, M@PFC can evade clearance by the immune system and prolong the circulation time in vivo; thus, enhancing their accumulation in tumors. PF3‐PPh 3 promotes high production of reactive oxygen species (ROS) and triggers immune cell death (ICD) in tumor cells under light exposure. Importantly, CpG enrichment in tumors can stimulate tumor cells to produce immune factors to assist in enhancing ICD effects. The synergistic effect combining the PDT properties of the aggregation‐induced emission (AIE)‐active photosensitizer and immunotherapy properties of CpG significantly delays tumor recurrence after surgery. In conclusion, this strategy achieves the synergistic activation of the immune system for anti‐tumor activity, providing a novel paradigm for the development of therapeutic nanodrugs to delay postoperative tumor recurrence.
Silver Nanowire Reinforced Conductive and Injectable Colloidal Gel for Effective Wound Healing Via Electrical Stimulation
Authors: Yaxin Du, Xu Yan, Sheng Chen, Zhengbao Zha, Wenshu Wu, Yonghong Song, Yadong Wu, Kangkang Li, Xingyu Liu, Yang Lu
Journal: Advanced Healthcare Materials (2023)

The remarkable biocapacity, injectability, and adaptability of colloidal gels lead to their widespread use in tissue engineering as irregular defect implants. However, multifunctionalities including electroconductivity and antibacterial property are highly required for colloidal gels. In addition, the inherently weak mechanical property of physically crosslinked colloidal gels limits their application. Herein, Ag nanowires (Ag NWs)-reinforced colloidal gels composed of biocompatible gelatin nanoparticles and polydopamine-modified Ag NWs through the controlled electrostatic assembly, which are injectable and conductive, are presented. 1D Ag NWs can significantly improve the mechanical and electrical properties of the colloidal gel while maintaining its inherent excellent injectability. Owing to the network of Ag NWs, the storage modulus and conductivity of the optimized Ag NW colloidal gel are 7.5 and 13 times higher, respectively, than those of the colloidal gel made up of polydopamine-modified Ag nanoparticles with equivalent Ag concentration. Further, this Ag NW colloidal gel can adapt to sharp wounds on skin, which accelerates the healing of an MRSA-infected wound via electrical stimulation.
ESMO Guidance for Reporting Oncology real-World evidence (GROW)
Authors: L. Castelo-Branco, A. Pellat, D. Martins-Branco, A. Valachis, J.W.G. Derksen, K.P.M. Suijkerbuijk, U. Dafni, T. Dellaporta, A. Vogel, A. Prelaj, R.H.H. Groenwold, H. Martins, R. Stahel, J. Bliss, J. Kather, N. Ribelles, F. Perrone, P.S. Hall, R. Dienstmann, C.M. Booth, G. Pentheroudakis, S. Delaloge, M. Koopman
Journal: Annals of Oncology (2023)
Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation
Authors: Xin Wang, Lina Sun, Biao Yang, Wenhua Li, Cangang Zhang, Xiaofeng Yang, Yae Sun, Xiaonan Shen, Yang Gao, Bomiao Ju, Yafeng Gao, Dan Liu, Jiapeng Song, Xiaoxuan Jia, Yanhong Su, Anjun Jiao, Haiyan Liu, Lianjun Zhang, Lan He, Lei Lei, WanJun Chen, Baojun Zhang
Journal: Journal of Clinical Investigation (2023)

Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.
T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice
Authors: Florian Wiede, Benjamin J. Shields, Sock Hui Chew Konstantinos Kyparissoudis, Catherine van Vliet, Sandra Galic, Michel L. Tremblay, Sarah M. Russell, Dale I. Godfrey, Tony Tiganis
Journal: Journal of Clinical Investigation (2023)
Fusogenic liposomes encapsulating mitochondria as a promising delivery system for osteoarthritis therapy
Authors: Hye-Ryoung Kim, Hui Bang Cho, Sujeong Lee, Ji-In Park, Hye Jin Kim, Keun-Hong Park
Journal: Biomaterials (2023)

Many attempts have been made to use mitochondria (MT) to treat human diseases; however, MT are large, making them difficult to deliver effectively. Therefore, a transfer strategy based on membrane fusion was established. Fusogenic mitochondrial capsules (FMCs) comprising a neutral lipid (PE), a cationic lipid (DOTAP), an aromatic lipid (Liss Rhod PE), and three types of liposome (FMC0, FMC1, and FMC2), were designed and synthesized. The amount of DOTAP, which affects membrane fusion efficiency, differed between FMC preparations. The characteristics of these FMCs were analyzed by DLS, TEM, and AFM, and the encapsulation and fusion efficiency between FMC-MT and FMC-chondrocytes were confirmed by FRET, mtDNA copy number, and CLSM, respectively. Compared with naked MT, delivery of FMCs to chondrocytes was faster and more efficient. Moreover, fusion was a more stable delivery method than endocytosis, as evidenced by reduced induction of mitophagy. In vitro and in vivo experiments revealed that FMCs reduced expression of inflammatory cytokines and MMP13, increased expression of extracellular matrix components, and promoted cartilage regeneration. These findings suggest that FMCs are a highly effective and promising strategy for delivery of MT to promote cartilage regeneration, and highlight their potential as a novel platform for MT transfer therapy.
Puzzle resolved: CFTR mediates chloride homeostasis by segregating absorption and secretion to different cell types
Authors: Burkhard Tümmler
Journal: Journal of Clinical Investigation (2023)

In the lungs, the cystic fibrosis transmembrane conductance regulator (CFTR) regulates ion transport in surface-airway epithelia and submucosal glands, thus determining airway surface liquid (ASL) volume and mucus hydration. In this issue of the JCI, Lei Lei and colleagues report that the CFTR-rich and barttin/Cl- channel-expressing ionocytes mediate chloride absorption across airway epithelia, whereas the more abundant basal cells and secretory cells mediate chloride secretion. Thus, CFTR-mediated secretion and absorption of chloride ions in the lung are segregated by cell type, which has implications for future molecular therapies for cystic fibrosis lung disease.
Chemical carcinogens: implications for cancer treatment
Authors: Shaofeng Liu, Mary Saunders, Tak W Mak
Journal: Journal of Clinical Investigation (2023)

Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.
Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment
Authors: Mei Huang, Yun Xia, Kaiwen Li, Feng Shao, Zhaoyi Feng, Tiancheng Li, Marjan Azin, Shadmehr Demehri
Journal: Journal of Clinical Investigation (2023)

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.
The Autonomous Pipeline Navigation of a Cockroach Bio-Robot with Enhanced Walking Stimuli
Authors: Songsong Ma, Yuansheng Chen, Songlin Yang, Shen Liu, Lingqi Tang, Bing Li, Yao Li
Journal: Cyborg and Bionic Systems (2023)

Tens of crawling bio-robots with cockroaches as the mobile platform have been developed with various functions. Compared with artificial crawling robots of the same size, they revealed better flexibility, larger payload, and stronger endurance. These features made bio-robots ideal for pipeline inspection scenarios because the advancements in locomotion mechanisms and efficient power systems are still hurdles for current artificial systems. In this study, we controlled the bio-robot to crawl in the confined dark pipeline and achieved autonomous motion control with the help of an onboard sensing system. Specifically, a micro-camera was mounted on the electronic backpack of the cockroach for image collection, and an IMU sensor was used to compute its body orientation. The electronic backpack transmitted images to the host computer for junction recognition and distance estimation. Meanwhile, the insect's habituation to electrical stimulation has long been an uncertain factor in the control of bio-robots. Here, a synergistic stimulation strategy was proposed to markedly reduce the habituation and increase the number of effective turning controls to over 100 times. It is also found that both the increase of payload and the application of stimulations could promote the metabolic rate by monitoring carbon dioxide release. With the integration of synergistic stimulation and autonomous control, we demonstrated the fully autonomous pipeline navigation with our cockroach bio-robot, which realized the cycle number of approximately 10 in a roll. This research provides a novel technology that has the potential for practical applications in the future.
SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling
Authors: Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou
Journal: Journal of Clinical Investigation (2023)

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.
Adenine crosses the biomarker bridge: from ‘omics to treatment in diabetic kidney disease
Authors: Yelena Drexler, Alessia Fornoni
Journal: Journal of Clinical Investigation (2023)

Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.
Alveolar epithelial regeneration in the aging lung
Authors: SeungHye Han, G R Scott Budinger, Cara J Gottardi
Journal: Journal of Clinical Investigation (2023)

Advancing age is the most important risk factor for the development of and mortality from acute and chronic lung diseases, including pneumonia, chronic obstructive pulmonary disease, and pulmonary fibrosis. This risk was manifest during the COVID-19 pandemic, when elderly people were disproportionately affected and died from SARS-CoV-2 pneumonia. However, the recent pandemic also provided lessons on lung resilience. An overwhelming majority of patients with SARS-CoV-2 pneumonia, even those with severe disease, recovered with near-complete restoration of lung architecture and function. These observations are inconsistent with historic views of the lung as a terminally differentiated organ incapable of regeneration. Here, we review emerging hypotheses that explain how the lung repairs itself after injury and why these mechanisms of lung repair fail in some individuals, particularly the elderly.
X-linked RBBP7 mutation causes maturation arrest and testicular tumors
Authors: Jingping Li, Huimei Zheng, Jiaru Hou, Jianhua Chen, Fengbin Zhang, Xiaohang Yang, Fan Jin, Yongmei Xi
Journal: Journal of Clinical Investigation (2023)

Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases.